More than 100 million people worldwide have Type 2 diabetes (TTDM) or its precursor impaired fasting glucose. TTDM compromises quality of life by causing serious microvascular and macrovascular complications (blindness, renal failure, heart attack, stroke) and premature death. Primary metabolic abnormalities in TTDM include impaired insulin secretion and insulin resistance. The pancreatic islet in people with TTDM is characterized by ~ 65% deficit in insulin secreting "beta" cells. Recent studies reveal hat this decreased number of beta cells leads to an abnormal pattern of insulin secretion which in of itself may contribute to insulin resistance. This link between the pattern of how insulin is secreted and the impact of this pattern on how well it works is the focus of the present application. In health insulin is secreted in discrete insulin secretory bursts occurring at ~5 minute intervals into the portal vein which directly exposes the liver to an insulin concentration wavefront of oscillations ranging in amplitude from 100-500 pmol/l at fasting to 1000-5000 pmol/l following meal ingestion. These oscillations are markedly decreased in size (but without change in frequency) in patients with TTDM. In Specific aim 1 we will seek to establish the underlying mechanisms leading to decreased insulin secretory bursts. We will study a newly developed rat model for TTDM by directly measuring pulsatile insulin secretion in the portal vein before and after development of diabetes and concurrently isolate islets from the same rats with the aim of establishing directly from these islets the mechanisms leading to the observed defective insulin secretion in vivo. Preliminary studies imply that a combination of endoplasmic reticulum stress and decreased available insulin stores leads to the deficit in pulse mass. In Specific Aim 2 we will seek to establish the consequences of the abnormal pulsatile pattern of linsulin secretion present in TTDM. To accomplish this we will measure hepatic glucose production following portal vein insulin delivery either in 1) normal pulsatile insulin infusion, 2) constant insulin infusion, 3) insulin infusion selected to reproduce that observed in patients with TTDM. Preliminary studies indicate that the pattern of insulin delivery present in TTDM leads to hepatic insulin resistance. In Specific Aim 3 we will seek to establish the potential mechanism(s) by which pulsatile insulin delivery enhances hepatic insulin signaling. Specifically, we will tests whether the pulsatile mode of insulin delivery avoids feedback inhibition of insulin signaling (avoiding AKT inhibition of IRS-2 activation). Specific Aim 3 will be undertaken with the additional guidance of Dr. Morris White at the Howard Hughes Medical Institute. [unreadable] [unreadable] [unreadable]